Hypercholesterolemia is known to be one of the prime risk factors for atherosclerosis and coronary heart disease, the leading cause of death and disability in western countries. The bile acid sequestrants seem to be moderately effective as antihypercholesterolemic agents but they must be consumed in large quantities, i.e., several grams at a time, and they are not very palatable.
Mevacor.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof. For example, simvastatin wherein the 8-acyl moiety is 2,2-dimethylbutyryl is an even more potent HMG CoA reductase inhibitor than lovastatin.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR1## wherein: Z is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R.sub.1 is: ##STR2## wherein Q is ##STR3## R.sub.3 is H or OH; and
R.sub.2 is hydrogen or methyl; and a, b, c, and d represent optional double bonds, especially where b and d represent double bonds or a, b, c, and d are all single bonds, provided that when a is a double bond, Q is ##STR4##
U.S. Pat. No. 4,517,373 discloses semi-synthetic hydroxy containing compounds represented by the above general formula wherein R.sub.1 is ##STR5##
U.S. Pat. No. 4,537,859 and U.S. Pat. No. 4,448,979 also disclose semi synthetic hydroxy-containing compounds represented by the above general formula wherein R.sub.1 is ##STR6##
These compounds are prepared by the action of certain microorganisms on the corresponding non-hydroxylated substrates. One such organism described in U.S. Pat. No. 4,537,859 is of the genus Nocardia.
Copending U.S. patent application Ser. No. 048,136 filed May 15, 1987 discloses HMG-CoA reductase inhibitors which include 6-desmethyl-6-hydroxymethyl- and 6-desmethyl-6-carboxylovastatin analogs. These compounds were formed by bioconversion of the sodium salt of lovastatin, or analogs having a 6-methyl group, using strains of the microorganism Nocardia autotrophica (MA 6180 and MA 6181). However, the bioconversion with this microorganism gave relatively low yields of the 6-hydroxymethyl analogs.
In the instant invention the novel microorganism Nocardia sp., (MA 6455) gives an improved yield of the 6-hydroxymethyl derivative.